Vascular lesions and ischemic damage play an important role in the pathology and clinical presentation of AD. A combination of AD and cerebral infarctions is the second most common type of dementia. Despite the importance of this mixed type of dementia, the interactions between these two pathological conditions remains under explored and is the focus of this project. Amyloid beta (Abeta) deposition in the brain can be due to increased CNS cellular production, related to endocytic-lysosomal abnormalities. However, brain soluble Abeta (sAbeta) peptide levels can also be modulated by their delivery from the systemic circulation and by their clearance from the brain across the blood-brain barrier (BBB). The central hypothesis of this project is that brain sAbeta clearance and its deposition in sporadic AD is influence by the presence of cerebral ischemic damage, amyloid deposition in each vessels and by the expression of different apolipoprotein (apo)E isoforms; as well as by endocytic/lysosomal abnormalities. Our preliminary results indicate that there is significance BB passage of Abeta peptides, both from the systemic circulation and following intra-ventricular injections out from the brain, which is influenced by whether the Abeta peptide is complexed to apoE and by the presence of ischemia. To test our hypothesis we plan: 1) Determine the influence of cerebro-vascular amyloid on BBB permeability of Abeta peptides using AD transgenic mouse models (APP/swe the influence of cerebro-vascular amyloid on BB permeability of Abeta peptides using AD transgenic mouse models (APP/swe/PS1/M146L, APP/E693Q and APP/A692G over-expressing mice) both from the systemic circulation and following intra-ventricular injections. Transgenic mice with endocytic abnormalities will also be studied. 2) The influence of both focal and global ischemia will be verified in vivo by MRI studies. It will be evaluated whether the amyloid deposition and ischemia are simply additive on pathology or if they act synergistically. In addition, the BB passage of Abeta peptides both from the mind and into the brain will be evaluated following ischemia in these mouse models. 3) The role of apoE on Abeta peptide clearance, following intraventricular injections, will be determined using apoE knockout mice and mice expressing human apoE2/3 or 4. The role of apoE2/3/4 on the clearance of fibrilllar, parenchymal Abeta deposits, will be determined by stereotactic intra-cerebral injections of Abeta peptides into the amygdala in these mice. The role of endocytic abnormalities on brain Abeta clearance, will also be studied by stereotactic intra-cerebral injections of Abeta peptides into transgenic mice. A dynamic tridimensional in vitro model of the human BBB will be used to corroborate the in vivo studies in mice. Together our studies will determine the contributions of vessel amyloid, ischemia, apoE isoforms and endocytic/lysosomal abnormalities to sporadic AD pathology.